Should my wife volunteer for Synexus osteoporosis trial?

Jump to follow-up

Synexus is "The world’s largest multi-national company entirely focused on the recruitment and running of clinical trials company that runs clinical trials and screening programmes".

I should say at the outset that I’m deeply impressed by our local GP practice. I can’t imagine a better GP than mine; he has the ideal mix of knowledge and empathy. I do, however, worry about the fragmentisation of the NHS and its creeping privatisation.

I came across Synexus because my wife had a letter (on our GP practice letterhead) inviting her to go for osteoporosis screening, and possibly to "take part in a study". Download the letter.

Notice that the form gives no idea of what the "study" might be. Notice also, more seriously, the small print on the second page of the form. Here it is in normal size print.

"If you contact Synexus and/or return the attached tear-off slip Synexus may, with your consent, use the data you provide for the purposes of informing you of the study, of medical products and processes that might be of interest to you. Your information will be held by, and access to it limited to, Synexus Ltd and/or companies within the Synexus group of companies and/or third parties acting on their behalf"

You are invited, in near-illegible small print, to allow all your medical data to be handed over to Synexus [see comment, below], and an unspecified number of other companies and third parties. It also gives the company permission to "use the data you provide for the purposes of informing you. . . of medical products and processes that might be of interest to you". This appears to mean that in the future you’ll be pestered with mailings that bypass your GP and advertise (private?) screening etc. For the purposes of screening there should be no need to hand over any data whatsoever (and the practice manager ensures me that they don’t).

My wife asked my advice about whether she should sign up for "the study" if invited to do so, so I asked the GP practice what the trial was about. Rather to my surprise, they didn’t know. Neither did Hertfordshire NHS. So I asked the National Osteoporosis Society, and they didn’t know either. After several emails and a phone call, I eventually got the details from Synexus.

I have two concerns about this. One is the argument that’s been raging about the value of indiscrimate screening, The case against it has been put perfectly in Margaret McCartney’s recent book, The Patient Paradox. There’s a good case that too much money is spent on people who are well, and not enough on those who are ill. Of course prevention is better than cure. The problem is that in many cases the screening tests aren’t accurate enough, so many people get diagnosed and treated when they are not actually ill.

On top of that, there is now a serious worry about screening tests promoted by private companies, for profit. Lifeline has been criticised, for good reasons. The men’s health charity, Movember, promotes PSA screening for prostate cancer, one of the most unreliable tests in existence. There is now a web site that collates evidence about private health screening. Many of the tests are available on the NHS, and the NHS advice about them is being re-written so that it gives information about risks as well as benefits.

The NHS advice on screening for osteoporosis is still ambiguous. The evidence for benefit of screening at age 60 is not clear.

The main question, though, is this. If my wife were offered an opportunity to "take part in a study", should she say yes, or no? My first inclination was to say yes. Clinical trials are the only way to find out whether treatments work or not. If people don’t volunteer for trials, we’ll never know. But before saying yes, one would want to know that the trial was organised properly, so that it could answer a relevant question. That’s why I was surprised when I found it so hard to discover the details. Nobody seemed to know even where the trial was registered. It’s no use searching trial registers for "Synexus": you need to know who is paying for it.

Eventually Dr John Robinson of Synexus turned out to be very helpful. The protocol number is 20070337 with a EudraCT number 2011-001456-11. The trial is registered at ClinicalTrails.gov and it has ethical approval. It’s a trial of a new osteoporosis treatment made by Amgen, AMG 785. It’s a monoclonal antibody against sclerostin, a protein that inhibits bone formation. It sounds like a good idea, but we won’t know how well it works until it’s been tested. The allocation of patients to AMG 785 or placebo is randomised and double blind. The patient Information sheet for participants looks pretty good to me.

Nevertheless, I have some reservations about the trial. First, its organisation is odd. “After taking AMG 785 or placebo for one year, all study participants will be taking denosumab for the following year”. Denusomab is another product of the same company, Amgen. It has already been approved by NICE.  When I asked Dr Robinson why this arrangement had been chosen, this is what he said.

"Previous studies have shown that the maximal benefit on bone density is seen after 12 months and that treatment after this period shows a lower increase, it is for this reason treatment with AMG 785 is for 12 months in this study.

Other studies have also shown benefit in further improving and maintaining the increase in bone density and reducing fracture risk by subsequently treating patients with Alendronate after 12 months of AMG 785. This study is investigating whether similar or better findings occur with denosumab."

This does not make any sense to me. If the object is to compare AMG 785 with denusomab, they should be compared side by side, not sequentially. That brings us straight to the main problem with the trial design. It asks the wrong question. What the doctor needs to know is whether AMG 785 is more effective than existing treatments, not whether it is better than placebo. When I asked Dr Robinson about this, he said

"To quote from the protocol: A placebo-controlled study was chosen because it permits a minimally confounded demonstration of efficacy and safety of AMG 785 in the treatment of PMO. Using an active control such as a bisphosphonate means that more patients have to be enrolled to show benefit from AMG 785. The study already plans to enrol 6000 women. Increasing this number would add to the time required to complete the study. In addition the use of a placebo control is also within regulatory guidelines. "

What this means, in plain English, is that they are expecting a rather small difference between AMG 785 and existing treatments. It would take a very large number of patients to show this difference. If the difference is indeed small, it would be hard to justify the (doubtless eye-watering) cost of AMG 795 (denusomab costs £185.00 per dose). Testing a new drug against placebo, or against a low dose of something not very effective, is one of the stratagems listed in Chapter 4, Bad trials, in Ben Goldacre’s Bad Pharma. It makes the new drug look good, but it asks the wrong question.

The National Osteoporosis Society should be an organisation to which patients could turn to for advice in cases like this. In this case they were not helpful. They didn’t know much about the trial. I hope that this is not related to the fact that they get a lot of funding from Synexus. I noticed too that one of their advisors is the infamous Professor Richard Eastell, who admitted in print to lying in a paper, about a drug for osteoporosis made by Proctor & Gamble. It’s getting quite hard to find a medical charity that isn’t in the pocket of Big Pharma. or quacks (or even occasionally, both).

Conclusion. The trial asks the wrong question. On those grounds alone, I think that my advice would be not to volunteer for the trial.

Follow-up

I should have mentioned an interesting and relevant Cochrane review, New treatments compared to established treatments in randomized trials (2012), The authors’ conclusions are as follows.

“Society can expect that slightly more than half of new experimental treatments will prove to be better than established treatments when tested in RCTs, but few will be substantially better. This is an important finding for patients (as they contemplate participation in RCTs), researchers (as they plan design of the new trials), and funders (as they assess the ’return on investment’).”

15 May 2013. As noted in the comments, Synexus has been censured by the Advertising Standards Authority, because the ASA judged that they did not give sufficient prominence to the fact that there advertising of free screening was actually a way to recruit people into clinical trials.